Urinary Transforming Growth Factor-Beta 1 as a Marker of Response to Immunosuppressive Treatment, in Patients With Crescentic Nephritis

Dimitrios S. Goumenos; Pantelitsa Kalliakmani; Sotiris Tsakas; Florentia Sotsiou; John G. Vlachojannis

Disclosures

BMC Nephrology. 2006;6 

In This Article

Abstract and Introduction

Abstract

Background: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β1 is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β1 levels in patients with crescentic nephritis could be used as a marker of response to treatment.
Methods: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β1 was estimated in biopsy sections by immunohistochemistry and urinary TGF-β1 levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β1 levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls.
Results: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β1 levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β1 was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β1 immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05).
Conclusion: Increased TGF-β1 renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β1 levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis.

Background

Crescentic nephritis is a type of glomerular disease characterized by crescent formation followed by a rapidly progressive course.[1] It can occur in cases with antibodies against glomerular basement membrane (anti-GBM disease), secondary to other glomerulonephritis and in patients with vasculitis and presence of antineutrophilic cytoplasmic antibodies (ANCA).[1] Proliferation of parietal cells of Bowman's capsule and macrophages stimulated by cytokines and growth factors is implicated in the development of cellular crescents that soon become fibrotic and result in irreversible damage.[2]

TGF-β represents a group of 25-kD proteins that are actively involved in the development and differentiation of various tissues and in the healing process after a tissue injury.[3] Three isoforms of TGF-β have been identified in mammalian species and TGF-β1 is the most commonly found in humans.[3] Normally, TGF-β1 release ceases by feedback mechanisms when the healing process has been completed.[3,4] However, if TGF-β1 release is not switched off, extracellular matrix components (ECM) are accumulated and tissue fibrosis occurs.[4] TGF-β1 is involved in the development of scarring in crescentic nephritis via activation of myofibroblasts from glomerular parietal epithelial cells.[5] Interstitial myofibroblasts also contribute to the development of fibrous crescents through their migration into the Bowman's space of glomeruli with disrupted capsules.[6] The implication of TGF-β1is further supported by the observation of amelioration of histologic damage in experimentally induced anti-GBM nephritis with the blockade of TGF-β1 action.[7]

Increased urinary excretion of TGF-β1 has been reported in experimentally induced crescentic nephritis that was related to a scarring process leading to end-stage renal disease.[8] Elevated urinary TGF-β1 levels have been observed in patients with crescentic nephritis and IgA nephropathy that were reduced after treatment with corticosteroids.[9] In the present study the renal expression and urinary excretion of TGF-β1 were examined in patients with crescentic nephritis in order to identify any potential relation of urinary TGF-β1 levels with the response to treatment with corticosteroids and cyclophosphamide.

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